JPS6272A - Benzo(a)phenazine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H, halogen, CH3, OH or alkoxy; R<2> is group of formula VI (R<5> is H, alkyl, cycloalkyl, benzyl or phenyl) or formula VII (R<6> and R<7> are H or lower alkyl or together with N form a heterocyclic group); R<3> and R<4> are H or lower alkyl; n is 2 or 3]. EXAMPLE:N-beta-dimethylaminoethyl 5-hydroxy-10-methoxy-9-methoxycarbonylbenzo [alpha]phenazine-6-carboxamide. USE:Medicinal drug having antitumor activity, useful for the remedy of cancer and enabling the solution of the problem of drug resistance. PREPARATION:The compound of formula I can be produced by condensing ethyl 3-hydroxy-1,4-dihydro-1,4-dioxo-2-naphthoate of formula V with the phenylenediamine compound of formula II and condensing the resultant compound of formula III with the alkylamine of formula IV in an organic solvent, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel benzo[α]phenazine-6-carpoxamide derivatives having antitumor activity, and provides compounds useful in the treatment of cancer.

Conventionally, benzo[(Z]phenazine derivatives known to have antitumor effects are 5science Reports)
of the Re5search In5tituto
of Iohoku University-C16
There is only one compound that was completely described in Vol. 1-2, pp. 18-26, 1969.

While Ming was trying to decide.

However, the above-mentioned and other existing anticancer drugs are still far from satisfactory in terms of efficacy and safety.

Ra title, 1. As a result of intensive studies aimed at improving the effectiveness of benzo[a]phenazine derivatives, the present inventors have discovered a benzo[a]cofenazine-6-carboxamide derivative that exhibits excellent antitumor activity and have completed the present invention. .

The present invention relates to the general formula 11 [wherein R' represents a hydrogen atom, a halogen atom, a methyl group, a hydroxyl group, or an alkoxy group, and R1 is the formula, -COOR' (wherein RM is a hydrogen atom, a straight chain or a branched chain alkyl group, cycloalkyl group, benzyl group or phenyl group) or the formula, (wherein R'' and R7 are the same or different and are a hydrogen atom, a lower alkyl group, or bonded to each other and together with an adjacent nitrogen atom) ) represents a group forming a heterocycle, R'' and R4 are the same or different and represent a hydrogen atom or a lower alkyl group, and n represents 2 or 3. A new benzo[α]phenazine-6-
The present invention relates to a carpoxamide derivative (hereinafter referred to as compound I).

In the present invention, halogen atoms include fluorine, chlorine,
It is bromine or iodine, and the alkoxy group includes lower alkoxy groups such as methoxy, ethoxy, propoxy, and butoxy groups. A straight chain or branched alkyl group is an alkyl group having 1 to 20 carbon atoms,
Examples include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, neopentyl group, hexyl group, decyl group, eifcyl group, and the like. The cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group. The lower alkyl group is an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, and the like.

The benzo[a-cofenazine-6-carboxamide derivative represented by the general formula I is a new compound, and is prepared from the known ethyl 3-hydroxy-1,4-dihydro-1°4-dioxo-2-naphtonite according to the following reaction formula. (wherein R'#R"tR', R' and n
is as described above).

(2) Namely, known ethyl 3-hydroxy-1,4-sihydro-1,4-dioxo-2-naphtonite was mixed with N,N'-carbonyldiimidazole in an organic solvent such as anhydrous tetrahydrofuran, N,N-dimethylformamide, and dioxane. Or, by treating with an acyl chloride such as acetyl chloride or pivaloyl chloride or a chloroformic acid ester such as ethyl chloroformate or benzyl chloroformate, and then condensing phenylenediamines represented by the formula ■, a heterocyclic compound represented by the formula ■ can be obtained.

When treating with acyl chlorides or chloroformates, it is preferred to use a basic catalyst such as triethylamine or pyridine.

The phenylenediamines of the formula I are known per se or can be obtained from known compounds by known methods. In the latter case, phenylenediamines can be obtained by, for example, esterifying 5-acetylaminosalicylic acid, nitrating it, then deacetylating it, and then reducing the nitro group. The phenylene diamines obtained here are preferably used in the above condensation reaction without being isolated as the case may be.

Compound (1) can be obtained by condensing the intermediate represented by formula (2) with a known alkylamine represented by (2). This condensation reaction can be carried out using, for example, benzene, toluene, N, N-
dimethylformamide, ethanol, dichloromethane,
It is carried out in an organic solvent such as tetrahydrofuran or without a solvent. The reaction temperature is 10 to 120°C, preferably 15 to 30°C. 6 If the reaction requires a long time, increase the temperature or add an alkali catalyst such as sodium alfuxite to increase the reaction time. can be shortened.

In the compound (1) thus produced, R8 can be converted by the following method.

That is, the corresponding ester can be obtained by esterifying the compound (1) in which R8 is a carboxyl group using, for example, diazomethane or diazoethane.

By transesterifying the compound (1) in which R1 is an alfkoxydicarbonyl group in an alcohol under an acid catalyst such as sulfuric acid or para-toluenesulfonic acid, a corresponding ester into which a solvent alkoxy group has been introduced can be obtained.

In addition, the compound I in which R1 is a purfukidicarbonyl group,
The corresponding carboxylic acid can be obtained by alkaline hydrolysis in a solvent such as water, alcohol, N,N-dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof.

Furthermore, a compound (■) in which R8 is an alfkhidicarbonyl group,
The corresponding carboxamide can be obtained by amitulysis using ammonia or a primary amine in an organic solvent such as dioxane or chloroform or without a solvent at normal pressure or under increased pressure.

Table 1 shows typical compounds I obtained by the present invention.

Take a look at the general formula related to the present invention! The novel benzo[alpha-cofenazine-6-carboxamide derivative shown in the following shows a strong survival effect on various tumor-bearing mice. It also makes it possible to treat cancers for which conventional anticancer drugs are not sufficiently effective and to solve the problem of drug resistance.

Next, the present invention will be explained in more detail by showing reference examples, working examples, and test examples.

Reference Example 1 Production of ethyl 5-acetylamino-2-ethoxybenzoate 5-acetylaminosalicylic acid 20g5 Ethyl iodide 41ml11. 50.5 g of anhydrous potassium carbonate in 3 parts of acetone
00ml and refluxed for 24 hours. After cooling, insoluble materials were filtered off, the filtrate was dried under reduced pressure, and the residue was recrystallized from ether to obtain the title compound.

m, p, 78-79°C Yield 13.68g Reference Example 2 Production of ethyl 5-acetylamino-2-ethoxy-4-nitrobenzoate Ethyl 5-acetylamino-2-ethoxybenzoate
Suspend 13.06 g of nitric acid in 50 parts of acetic anhydride, and add 3 parts of fuming nitric acid.
ml was added dropwise while cooling with water. After completion of the dropwise addition, the mixture was stirred for 30 minutes under water cooling and for 4 hours at room temperature. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain the title compound.

118-120°C Yield 6.35g Reference Example 3 Production of methyl 5-amino-2-ethoxy-4-nitrobenzoate 1.5g of ethyl 5-acetylamino-2-ethoxy-4-nitrobenzoate was dissolved in 5% sulfuric acid. -methanol (V/
V) Suspended in 50ynll and refluxed for 4 hours. After cooling, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain the title compound.

ff1. I), 156-157°C Yield 1.01g Reference Example 4 Production of ethyl 10-ethoxy-5-hydroxy-9-methoxycarbonylbenzoxylate (1) Methyl 5-amino-2-ethoxy-4-nitrobenzoate 873mg and 50 mg of 10% palladium-hydrogen was suspended in 50 ml of ethanol, and hydrogenated at room temperature and normal pressure. The catalyst was filtered off, and the filtrate was dried under reduced pressure to obtain crude methyl 4,5-diamino-2-ethoxybenzoate.

(2) Ethyl 3-hydroxy-1,4-dihydro-1
.

895 mg of 4-dioxo-2-naphtonite was added to N. N-
Dissolved in 10 ml of dimethylformamide, N. Add 620 mg of N″-carbonyldiimidazole and let the mixture cool for 2 hours at room temperature.
Stir for hours. Add to this the crude methyl obtained in (1) above 4.
10tdN of 5-diamino-2-ethoxybenzoate
．． A N-dimethylformamide solution was added under water cooling, and the mixture was stirred at room temperature overnight. 200 mQ of ethanol was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to obtain the title compound.

m. p. 270-273°C Yield: 531 mg Using the corresponding alkyl iodide, the following compound was obtained by treating in the same manner as in Reference Example 1.

Reference example 5 Propyl 5-acetylamino-2-propoxybenzoate oily substance Reference example 6 Butyl 5-acetylamino-2-butoxybenzoate oily substance For corresponding acetylaminobenjetra A, Reference example 2
The following compound was obtained by treatment in the same manner as above.

Reference Example 7 Propyl 5-acetylamino-4-nitro-2-propoxybenzoate m. p. 89-91°C Reference Example 8 Butyl 5-acetylamino-2-butoxy-4-nitrobenzoate m. p. 82-83°C Reference Example 9 Methyl 4-acetylamino-2-hydroxy-5-nitrobenzoate ff1. p. 171-11°C Reference Example 10 Methyl 4-acetylamino-2-chloro-5-nitrobenzoate m. p. 132.5. ~134. 0°C reference example 2. For each of the acetylaminonitrobenzoate obtained in Reference Example 7, Reference Example 8, Reference Example 9 or Reference Example 10,
The following compounds were obtained by treating in the same manner as in Reference Example 3 using various alcohols.

Reference example 11 Ethyl 5-amino-2-ethoxy-4-nitrobenshade m, p, 140-141°C Reference example 12 Butyl 5-amino-2-ethoxy-4-nitrobenzoate m, p, 90-92°C Reference Example 13 Methyl 5-amino-4-nitro-2-propoxybenzoate m, p, 132-134°C Reference example 14 Ethyl 5-amino-4-nitro-2-propoxybenzoate 111, p, 101-102°C Reference example 15 Propyl 5-amino-4-nitro-2-propoxybenzoate m, p, 105-106°C Reference example 16 Butyl 5-amino-4-nitro-2-propoxybenzoate m, p, 72-75°C Reference example 17 Methyl 5 -Amino-2-butoxy-4-nitrobenzoate m, p, 121-122°C Reference example 18 Butyl 5-amino-2-butoxy-4-nitrobenzoate m, p, 67-68°C Reference example 19 Methyl 4 -Amino-2-hydroxy-5-nitrobenzoate tll, p, 197-199°C Reference example 20 Methyl 5-amino-2-chloro-4-etropenzoate m, p, 225-226°C Reference example 21 5 -Production of amino-2-methoxy-4-nitrobenzoic acid 13.57 g of methyl 5-amino-2-methoxy-4-nitrobenzoate was suspended in 250 ml of dioxane,
A solution of 4.36 g of potassium hydroxide and 25 ml of water was added and refluxed for 4 hours.Next, 7 ml of concentrated hydrochloric acid was added to the reaction mixture, the solvent was distilled off under reduced pressure, and dioxane was added to the residue.
Refluxed for an hour. Insoluble matter was filtered off to obtain crystals of the title compound precipitated from the filtrate.

m, p, 252-255°C Yield 10.99g Reference Example 22 Production of 1-(5-amino-2-methoxy-4-nitrobenzoyl)pyrrolidine 5-amino-2-methoxy-4-nitrobenzoic acid 4.2
4 g was dissolved in 30 ml of N,N-dimethylformamide, and 3.24 g of N,N'-carbonyldiimidazole was added at room temperature. After 30 minutes, 5 ml of pyrrolidine was added and stirring was continued for 2 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the title compound.

m, p, 159-162°C Yield: 4.16g The following compound was obtained by using dimethylamine or neopentyl alcohol in place of pyrrolidine and treating in the same manner as in Reference Example 22.

Reference example 23 N,N-dimethyl 5-amino-2-methoxy-4-nitrobenzamide m, p, 209-211°C Reference example 24 Neopentyl 5-amino-2-methoxy-4-nitrobenzoate m, p, 173- 177°C Reference Example 25 Production of 5-amino-2-methoxy-4-nitrobenzamide Methyl 5.66 g of 5-amino-2-methoxy-4-nitrobenzoate was dissolved in 200 ml of dioxane,
50 ml of 8% aqueous ammonia was added and left at room temperature for 40 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from dioxane to obtain the title compound.

m, p, 250-257℃ Yield 4.30g Reference Example 2
Preparation of 6 N-ethyl 5-amino-2-methoxy-4-nitrobenzamide It was obtained in the same manner as in Reference Example 25 using a 70% aqueous ethylamine solution.

m, p, 235-239°C Reference Example 27 Production of phenyl 5-amino-2-methoxy-4-nitrobenzoate 5-amino-2-methoxy-4-nitrobenzoic acid 5.5
Suspend 5g in 40ml of benzene, add 40ml of thionyl chloride
1 was added and the mixture was refluxed for 4 hours. Next, excess thionyl chloride and the solvent were distilled off, and the residue was dissolved in 40 mQ of benzene to obtain 12.3 g of phenol, 15 g of triethylamine,
3 mQ was added under water cooling, and the mixture was stirred under water cooling for 30 minutes and at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was diluted with 1
After washing with 0% aqueous sodium hydroxide and then with water, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the benzene eluted fractions were collected and recrystallized from methanol to obtain the title compound.

m, p, 130-132°C Yield 2.55g Reference Example 4
Similarly, by replacing methyl 5-amino-2-ethoxy-4-nitrobenzoate with the corresponding 5-amino-4-nitrobenzoic acid ester, intermediates represented by the following formula (1) were obtained.

Reference example 28 f) 10-ethoxy-9-ethoxycarbonyl-
5-Hydroxybenzo[(Z]phenazine-6-carboxylate m, p, 160-162°C Reference Example 29 Ethyl 9-butoxycarbonyl-10-ethoxy-5
-Hydroxybenzo[α]phenazine-6-carboxylate m, p, 122.5-123.5°C Reference Example 30 Ethyl 5-hydroxy-9-methoxycarbonyl-1
0-Propoxybenzo[(21 phenazine-6-carboxylate m, p, 143-145°C Reference Example 31 Ethyl 9-ethoxycarbonyl-5-hydroxy-1
0-propoxybenzo[αcohuenazine-6-carboxylate ff1. 117-119°C Reference Example 32 Ethyl 5-hydroxy-10-propoxy-9-propoxycarbonylbenzo[α]phenazine-6-carboxylate m, p, 153-155°C Reference Example 33 Ethyl 9-butoxycarbonyl - 10-propoxybenzo[a]phenazine-6-carboxylate m. p. 119-120°C Reference Example 34 Ethyl 10-butoxy-5-hydroxy-9-methoxycarbonyl-benzoboxylate m. p. 143-144°C Reference Example 35 Ethyl 10-butoxy-9-butoxycarbonyl-5
-Hydroxybenzo[α-cofenazine-6-carboxylate m. p. 122-124°C Reference Example 36 Ethyl 5-hydroxy-9-methoxycarbonyl-1
0-Methylbenzo[α-cofenazine-6-carboxylateffi. p. 295-299°C Reference Example 37 Ethyl 5.10-dihydroxy-9-methoxycarbonylbenzo[(Z Production of cofenadine-6-carboxylate Methyl 5-amino-2-ethoxy-4-nitrobenzoate replaced with methyl 4-amino -2-hydroxy-
It was obtained in the same manner as in Reference Example 4 using 5-nitrobenzoate.

m, p, 300°C or higher Reference Example 3B Ethyl 9-ethoxycarbonyl-benzo[α Production of cofenazine-6-carboxylate Methyl 5-amino-2-ethoxy-4-nitrobenzoate replaced with ethyl 4-amino-3-nitrobenzoate It was obtained by processing in the same manner as in Reference Example 4. m. p
．． 210-213°C Reference Example 39 Ethyl 5-Hydroxy-10-methoxy-9-phenoxycarbonylbenzo[Mycofenazine-6-carboxylate Production Methyl 5-amino-2-ethoxy-4-nitrobenzoate Phenyl 5- Amino-2-methoxy-
It was obtained in the same manner as in Reference Example 4 using 4-nitrobenzoate.

m. 2. 171-173°C Reference Example 40 Production of ethyl 10-chloro-5-hydroxy-9-methoxycarbonylbenzosylate Methyl 5-amino-2-chloro-4-etropenzoate was reduced with iron-hydrochloric acid in ethanol. crude methyl 4
, 5-diamino-2-chloropenzoate was obtained by the same treatment as in Reference Example 4(2).

m. p. 225-226℃ Reference Example 41 Ethyl 9-katoxy5-hydroxybenzo[α
] Production of phenazine-6-carboxylate Methyl 4
．． 3 instead of 5-diamino-2-ethoxybenzoate
．． It was obtained in the same manner as in Reference Example 4(2) using 4-diaminobenzoic acid.

m. p. 300°C or higher Reference Example 42 Production of 4,5-diamino-2-methoxybenzamide 5-amino-2-methoxy-4-nitrobenzamide 3
．． 04g and 110mg of 10% palladium-carbon were suspended in 300ml of methanol and hydrogenated at normal pressure and 60°C. The catalyst was filtered off, and the filtrate was concentrated to obtain crystals of the title compound.

m. p. 181-183℃ Yield 2.18g Reference Example 4
3 Preparation of N-ethyl 4.5-diamino-2-methoxybenzamide N-ethyl 5-amino-2-methoxy-4-nitrobenzamide was obtained in the same manner as in Reference Example 42.

m. p. 65-67°C Reference Example 44 Ethyl 5-hydroxy-10-methoxy-9-methoxycarbonylbenzo[α Production of cofenadine-6-carpoxylate (1) Ethyl 3-hydroxy-1.4-dihydro-1
, 4-dioxo-2-naphthonito2. 48 g and 1.5 ml of triethylamine were dissolved in 10 ml of anhydrous tetrahydrofuran, one portion of ethyl chloroformate was added dropwise at below 5° C., and the mixture was stirred at room temperature for 2 hours. The produced solid was filtered off, and the filtrate was dried under reduced pressure to give crude ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-
2-naphtonite was obtained.

(2) 2.16 g of methyl 4.5-diamino-2-methoxybenzoate was added to N.I. N-dimethylformamide 7m
N,N-dimethylformamide 7 of the crude ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2-naphtonite obtained in (1) above, dissolved in
ynll solution was added under water cooling and stirred for 2 hours. Next, 100 ml of ethanol was added and the precipitated crystals were collected by filtration.
Recrystallization from chloroform-ethanol gave the title compound.

m. p. 202.5-207°C Yield 3.66 g Methyl 4.5-Diamino-2-methoxybenzoate was replaced with orthophenylenediamine obtained in Reference Example 42 or Reference Example 43, and treated in the same manner as in Reference Example 44. Intermediates shown in the following 2) were obtained.

Reference Example 45 Ethyl 9-carbamoyl-5-hydroxy-10=methoxybenzo[a]phenazine-6-carboxylate m, p, 300°C or higher Reference Example 46 Ethyl 9-ethylcarbamoyl-10-methoxybenzo[(Z] Phenazine-6-carboxylate m.p. 190-193°C Reference Example 47 Production of ethyl 5-hydroxy-10-methoxy-9-dimethylcarbamoylbenzoboxylate N.N-dimethyl 5-amino-2-methoxy-4 - 3.62 g of nitropenzamide and 10% palladium -
Suspend 150 mg of carbon in 140 ml of ethanol,
Hydrogenation was carried out at normal pressure and 70-80°C. Filter the catalyst,
The filtrate was dried under reduced pressure to obtain crude N. N-dimethyl 4.5-
Diamino-2-methoxybenzamide was obtained and dissolved in tetrahydrofuran 30rd.

Separately ethyl 3-hydroxy-1,4-dihydro-1,
Reference Example 4: 3.41 g of 4-dioxo-2-naphtonite
4(1) to obtain ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2
-Naphtonite was obtained, dissolved in 10 ml of tetrahydrofuran, and cooled with water to obtain the previously prepared N,N-dimethyl 4,5
-Diamino-2-methoxybenzamide was added to a tetrahydrofuran solution, and the mixture was stirred at room temperature for 2 hours. 100 mQ of ethanol was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from chloroform-ethanol to obtain the title compound.

m. p. 224-227℃ Yield 3.70gN,N-
Dimethyl 5-amino-2-methoxy-4-nitrobenzamide was replaced with the corresponding orthonitroaniline and treated in the same manner as in Reference Example 47 to obtain intermediates represented by the following formula (1).

Reference Example 4B Ethyl 5-hydroxy-10-methoxy-9-(
1-pyrrolidinocarbonyl)benzo[(Zl phenazine-6-carboxylate m.p. 221-224°C Reference Example 49 Ethyl 5-hydroxy-10-methoxy-9-neopentyloxycarbonylbenzo[(21 phenazine-6
-carboxylate m. p. 153-157°C Example I N-β-dimethylaminoethyl 5-hydroxy-10
-Methoxy-9-methoxycarbonylbenzo[alpha] Production of cofenazine-6-carboxamide Ethyl 5-hydroxy-10-methoxy-9-methoxycarbonylbenzo[+2]phenazine-6-carboxylate 20.32
Dissolve N. g in 500 ml of Hensen. N-dimethylethylenediamine 11+nQ was added and the mixture was refluxed for 2 hours.

The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-ethanol to obtain the title compound.

m. p. 195-196℃ Yield 22. Using 17g of the corresponding intermediate represented by formula (2), the following compound I was obtained by processing in the same manner as in Example 1.

Example 2 N-β-dimethylaminoethyl 5-hydroxy-9-
Carboxybenzo[alpha cohuenazine-6-carpoxamide m. p. 245-246°C Example 3 N-β-dimethylaminoethyl 9-ethoxycarbonyl-5-hydroxybenzo[α]phenazine-6-carpoxamideffi. 1), 200-204°C Example 4 N-β-dimethylaminoethyl 10-chloro-5-hydroxy-9-methoxycarbonylbenzo[(Z]phenazine-6-carboxamide ff1.p. 217-221°C Example 5 N-β-dimethylaminoethyl 5-hydroxy-9-
Methoxycarbonyl-phenazine-6-carboxamide m, p, 219-220°C Example 6 N-β-dimethylaminoethyl 5-hydroxy-10
-methoxy-9-phenoxycarbonylbenzo[a cohuenazine-6-carboxamide m, p, 189-19
0°C Example 7 N-β-dimethylaminoethyl 5-hydroxy-10
-Methoxy-9-neopentyloxycarbonylbenzo[mycofenazine-6-cartopoxamide m, p, 1
86-188°C Example 8 N-β-dimethylaminoethyl 9-carbamoyl-5
-hydroxy-10-methoxybenzo[a cofenazine-6-carboxamide m, p, 234-237°C Example 9 N-β-dimethylaminoethyl 9-ethylcarbamoyl-5-hydroxy-10-methoxybenzo[mycofenazine-6 -carboxamide ff14), 230-233°C Example 1O N-β-dimethylaminoethyl 5-hydroxy-10
-Methoxy-9-dimethylcarbamoylbenzo[mycofenazine-6-carboxamide”, p. 202-20
4°C Example 11 N-β-dimethylamine ethyl 5-hydroxy-10
-Methoxy-9-(1-pyrrolidinocarbonylnzo[α]phenazine-6-carpoxamide m.p. 22
8-230°C Example 12 N-β-dimethylamine ethyl 10-ethoxy-5-
Hydroxy-9-methoxycarbonylbenzo[α]phenazine-6-carpoxamide 111, 1), 170~
172°C Example 13 N-β-dimethylaminoethyl 10-ethoxy-9-
Ethoxycarbonyl-[α]phenazine-6-carpoxamide m. p. 15
8 to 160°C Example 14 N-β-dimethylamine ethyl 9-butoxycarbonyl-10-ethoxy-5-hydroxybenzo[(Z]phenazine-6-carboxamide m.p. 138 to 140°C Example 15 N-β -dimethylaminoethyl 5-hydroxy-9-
Methoxycarbonyl-[α]phenazine-6-carpoxamide m. p. 18
7-188°C Example 16 N-β-dimethylaminoethyl 9-ethoxycarbonyl-5-hydroxy-10-propoxybenzo[(Z]
Phenazine-6-carboxamide m. p. 154-1
55°C Example 17 N-β-dimethylaminoethyl 5-hydroxy-10
-Propoxy-9-propoxycarbonylbenzo[α-cofenazine-6-carpoxamideff11. 114～
115°C Example 1B N-β-dimethylaminoethylbonyl 5-hydroxy-10-propoxybenzo[(Z
] Phenazine-6-carboxamide m. p. 65-6
6°C Example 19 N-β-dimethylaminoethyl 10-butoxy-5-
Hydroxy-9-methoxycarbonylbenzo[a cofenadine-6-carboxamide m. p. 171-17
2°C Example 2O N-β-dimethylaminoethyl 10-butoxy-9-
Butoxycarbonyl-[acofenazine-6-carboxamideff11.
102-104°C Example 21 N-β-dimethylaminoethyl 5,10-dihydroxy-9-methoxycarbonylbenzodine-6-carpoxamide m, p, 250°C (decomposition) Example 22 N-β-ethylaminoethyl 5 -Hydroxy-10-
Preparation of methoxy-9-methoxycarbonylbenzo[α]phenazine-6-carpoxamide A product was obtained in the same manner as in Example 1, using N-ethylethylenediamine in place of N,N-dimethylethylenediamine.

m, 9.140-142°C Example 23 N-β-diethylamine ethyl 5-hydroxy-10
-Preparation of methoxy-9-methoxycarbonylbenzo[α]phenazine-6-carpoxamideN. N. in place of N-dimethylethylenediamine. It was obtained in the same manner as in Example 1 using N-diethylethylenediamine.

m. p. 164-165°C Example 24 N-7-dimethylaminopropyl-5-hydroxy-1
Preparation of 0-methoxy-9-methoxycarbonylbenzo[α]phenazine-6-carpoxamideN. N. in place of N-dimethylethylenediamine. N-dimethyl-1,3-
It was obtained in the same manner as in Example 1 using propanediamine.

111, 2. 143-145°C Example z5 N-β-dimethylaminoethylbonyl-5-hydroxy-10-methoxybenzo[α]
Production of phenazine-6-carpoxamide N-β-dimethylaminoethyl 5-hydroxy-10- obtained in Example 1
21.52 g of methoxy-9-methoxycarbonylbenzo was suspended in 400 ml of n-butanol to which 8 ml of concentrated sulfuric acid was added, and the mixture was refluxed for 5 hours. n-Butanol was distilled off under reduced pressure, the residue was added to double-blind water, and the resulting solid was collected by filtration and recrystallized from chloroform-ethanol to obtain the title compound.

m. p. 116-117°C Yield: 21.41 gn The following corresponding compound I was obtained by treating in the same manner as in Example 25, using another alcohol in place of gn-butanol.

Example 26 N-β-dimethylaminoethyl 9-ethoxycarbonyl-5-hydroxy-10-methoxybenzo[α]phenazine-6-carpoxamide m,p. 171-174°C Example 27 N-β-dimethylaminoethyl 5-hydroxy-10
-Methoxy-9-propoxycarbonylbenzo[αcohuenazine-6-carpoxamide m. p. 164-1
66°C Example 2B N-β-dimethylamine ethyl 5-hydroxy-10
-methoxy-9-inpropoxycarbonylbenzo[α
] Phenazine-6-carpoxamide m. p. 162～
163°C Example 29 N-β-dimethylaminoethyl 9-isobutoxycarbonyl-5-hydroxy-10-methoxybenzo[(Z
l phenazine-6-carboxamide m. p. 149～
151°C Example 3O N-β-dimethylaminoethyl 5-hydroxy-10
-Methoxy-9-pentyloxycarbonylbenzo”, p. 119-120°C Example 31 N-β-dimethylaminoether 5-hydroxy-10
-Methoxy-9-isopentyloxycarbonylbenzo[αcohuenazine-6-carboxamide m. 9. 14
0-143°C Example 32 N-β-dimethylaminoethyl 9-cyclopentyloxycarbonyl 5-hydroxy-10-methoxy-benzo[α]phenazine-6-carpoxamide m. p.
155-158°C Example 33 N-β-dimethylaminoethyl 9-hexyl carbonyl-5-hydroxy-10-methoxybenzo[α
Cofenadine-6-carboxamide m, p, 95-9
6°C Example 34 N-β-dimethylaminoethyl 9-cyclohexyloxycarbonyl-5-hydroxy-10-methoxybenzo[α]phenazine-6-carpoxamide ff1. I)
, 155-158°C Example 35 N-β-dimethylaminoethyl 9-heptyloxycarbonyl-zo[(2]phenazine-6-carpoxamide + 11.p
．． 88-89°C Example 36 N-β-dimethylamine ethyl 5-hydroxy-10
-methoxy-9-octyloxycarbonylbenzo[(
2] Phenazine-6-carboxamide m. p. 98
~103°C Example 37 N-β-dimethylaminoethyl 9-decyloxycarbonyl-5-hydroxy-10-methoxybenzo[α cofenadine-6-carpoxamide m. p. 97-1
00°C Example 38 N-β-dimethylamine ethyl 5-hydroxy-10
-Methoxy-9-pentadecyloxyluponylbenzo[α]phenazine-6-carpoxamide m. p. 96
~98.5°C Example 39 N-β-dimethylaminoethyl 9-benzyloxycarbonyl-5-hydroxy-10-methoxybenzo[(
2] Phenazine-6-carboxamide m. p. 125
~127°C Example 4O N-β-dimethylaminoethyl 5-hydroxy-10
-Methoxy-9-methylcarbamoylbenzo[α]phenazine-6-carpoxamide N- obtained in Example 1
β-Dimethylaminoethyl 5-hydroxy-10-methoxy-9-methoxycarbonylbenzo[a]phenazine-6-carboxamide 2. 24 g was added to 900 g of dioxane.
100ml of 40% methylamine aqueous solution
was added and left at room temperature for 6 days. The reaction solution was dried under reduced pressure, and the residue was recrystallized from chloroform-ethanol to obtain the title compound.

m. p. 245-248℃ Yield 2. The following corresponding compound was obtained by processing in the same manner as in Example 40, using another amine in place of OOg methylamine.

Example 41 N-β-dimethylaminoethyl 5-hydroxy-10
-methoxy-9-propylcarbamoylbenzo[alpha]cohuenazine-6-carboxamide m. p. 224-2
26.5°C Example 42 N-β-dimethylamine ethyl 9-butylcarbamoyl-5-hydroxy-10-methoxybenzo[α]phenazine-6-carpoxamide m. p, 221-224°C Example 43 N-β-dimethylaminoethyl 5-hydroxy-9-
Production of methoxycarbonylbenzo[α]phenazine-6-carpoxamide N-β-dimethylaminoethyl 9-carboxy-5-hydroxybenzo[(2]phenazine-6 obtained in Example 2)
- 1.45 g of carpoxamide was suspended in 100 ml of methanol and excess diazomethane-ether solution was added.

The reaction solution was dried under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform-methanol (
The fractions eluted with 10:1) were collected and recrystallized from methanol to obtain the title compound.

m. p. 200-203℃ Yield 0. 71g Example 44 N-β-dimethylaminoethyl 5-hydroxy-10-methoxybenzo[α Preparation of α-cofenazine-6-carpoxamide N-β-dimethylaminoethyl 5-hydroxy-10-methoxy-9 obtained in Example 1 -Methoxycarbonylbenzo[(Z]phenazine-6-carpoxamide 4.48g
was suspended in 80 ml of methanol, and 1.0 ml of potassium hydroxide was added.
A solution of 18 g and 80 td of water was added and refluxed for 5 hours. 350 ml of water and dry ice were added, and the precipitated crystals were collected by filtration, dried, and recrystallized from N,N-dimethylformamide-ethanol to obtain the title compound.

m, p, 232-237°C Yield: 3.90 g Test example [Test using lymphocytic leukemia P38B (1) Experimental animal P388 leukemia cells passaged in DBA/2 female mice were injected intraperitoneally in 1 x 10 cells each. Transplanted CDF, female mice (
(5-6 week old, 1 body weight: 17-20 g) was used. The day of transplantation was defined as day 0.

(2) Administration method Compound I was suspended in 0.5% gum arabic/physiological saline and intraperitoneally administered once a day, a total of 5 times from day 1 to day 5. 5-fluorouracil was used as a comparative drug, dissolved in physiological saline, and administered in the same manner. In the same manner, only 0.5% gum arabic/physiological saline was administered to the control group.

The treatment group administered Compound I or the comparative drug consisted of 8 animals per group;
The control group consisted of 16 animals.

(3) Evaluation method Efficacy was evaluated based on the efficacy criteria of the US National Cancer Institute (MCI).

Surviving animals in each group were recorded for 30 days, and T/CX100 (%) was calculated from the median survival days (T) of the treatment group and the median survival days (C) of the control group.

It is considered valid when the T/CX100 value is 125 or more.

(4) Test results The test results are shown in Table-2.

Compound I of the invention showed large T/CX100 values and efficacy over a wide range of doses.

Table-27 Effect on mouse P388 (Note)

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom, a halogen atom, a methyl group,
It represents a hydroxyl group or an alkoxy group, and R^2 represents the formula, -COOR^5 (wherein R^5 represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, a benzyl group, or a phenyl group. ) or formulas, ▲numeric formulas, chemical formulas, tables, etc.▼ (In the formulas, R^6 and R^7 are the same or different and are hydrogen atoms, lower alkyl groups, or bonded to each other to form a heterocyclic ring together with adjacent nitrogen atoms. ), R^3 and R^4 are the same or different and represent a hydrogen atom or a lower alkyl group, and n represents 2 or 3. ] A benzo[a]phenazine derivative represented by.